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Originally published online as doi:10.1189/jlb.0608352 on November 21, 2008

Published online before print November 21, 2008
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(Journal of Leukocyte Biology. 2009;85:518-525.)
© 2009 by Society for Leukocyte Biology

DCIR is endocytosed into human dendritic cells and inhibits TLR8-mediated cytokine production

Friederike Meyer-Wentrup, Alessandra Cambi, Ben Joosten, Maaike W. Looman, I. Jolanda M. de Vries, Carl G. Figdor and Gosse J. Adema1

Department of Tumor Immunology, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

1 Correspondence: Department of Tumor Immunology, Radboud UMC Nijmegen, NCMLS/278 TIL, Post Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: g.adema{at}ncmls.ru.nl

C-type lectin receptors (CLRs) expressed on APCs play a pivotal role in the immune system as pattern-recognition and antigen-uptake receptors. In addition, they may signal directly, leading to cytokine production and immune modulation. To this end, some CLRs, like dectin-1 and dendritic cell immunoreceptor (DCIR), contain intracellular ITIMs or ITAMs. In this study, we explored expression and function of the ITIM-containing CLR DCIR on professional APCs. DCIR is expressed on immature and mature monocyte-derived DCs (moDC) but also on monocytes, macrophages, B cells, and freshly isolated myeloid and plasmacytoid DCs. We show that endogenous DCIR is internalized efficiently into human moDC after triggering with DCIR-specific mAb. DCIR internalization is clathrin-dependent and leads to its localization in the endo-/lysosomal compartment, including lysosome-associated membrane protein-1+ lysosomes. DCIR triggering affected neither TLR4- nor TLR8-mediated CD80 and CD86 up-regulation. Interestingly, it did inhibit TLR8-mediated IL-12 and TNF-{alpha} production significantly, and TLR2-, TLR3-, or TLR4-induced cytokine production was not affected. Collectively, the data presented characterize DCIR as an APC receptor that is endocytosed efficiently in a clathrin-dependent manner and negatively affects TLR8-mediated cytokine production. These data provide further support to the concept of CLR/TLR cross-talk in modulating immune responses.

Key Words: cell surface molecule • pattern recognition receptor • C-type lectin • receptor cross-talk




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